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Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p><jats:italic>Chlamydia trachomatis<\/jats:italic> (<jats:italic>C. trachomatis<\/jats:italic>) is a Gram-negative obligate intracellular bacterium that causes reproductive tract complications in women, including ectopic pregnancies and tubal factor infertility. We hypothesized that mast cells, which are common at mucosal barriers, may contribute to responses to <jats:italic>Chlamydia<\/jats:italic> infection and aimed to define human mast cell responses to <jats:italic>C. trachomatis<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Human cord blood-derived mast cells (CBMCs) were exposed to <jats:italic>C. trachomatis<\/jats:italic> to assess bacterial uptake, mast cell degranulation, gene expression, and production of inflammatory mediators. The role of formyl peptide receptors and Toll-like receptor 2 (TLR2) were investigated using pharmacological inhibitors and soluble TLR2. Mast cell-deficient mice and littermate controls were used to examine the <jats:italic>in vivo<\/jats:italic> role of mast cells in influencing the immune response to <jats:italic>Chlamydia<\/jats:italic> infection in the female reproductive tract.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>C. trachomatis<\/jats:italic> bacteria were taken up by human mast cells but did not replicate efficiently inside CBMCs. <jats:italic>C. trachomatis<\/jats:italic>-activated mast cells did not degranulate but maintained viability and exhibited cellular activation with homotypic aggregation and upregulation of ICAM-1. However, they significantly enhanced the gene expression of <jats:italic>IL1B<\/jats:italic>, <jats:italic>CCL3<\/jats:italic>, <jats:italic>NFKB1<\/jats:italic>, <jats:italic>CXCL8<\/jats:italic>, and <jats:italic>IL6<\/jats:italic>. Inflammatory mediators were produced, including TNF, IL-1\u03b2, IL-1RA, IL-6, GM-CSF, IL-23, CCL3, CCL5, and CXCL8. Endocytic blockade resulted in reduced gene expression of <jats:italic>IL6<\/jats:italic>, <jats:italic>IL1B<\/jats:italic>, and <jats:italic>CCL3<\/jats:italic>, suggesting <jats:italic>C. trachomatis<\/jats:italic> induced mast cell activation in both extracellular and intracellular locations. The IL-6 response to <jats:italic>C. trachomatis<\/jats:italic> was reduced when CBMCs were treated with <jats:italic>C. trachomatis<\/jats:italic> coated with soluble TLR2. Mast cells derived from TLR2-deficient mice also demonstrated a reduced IL-6 response to <jats:italic>C. muridarum<\/jats:italic>. Five days following <jats:italic>C. muridarum<\/jats:italic> infection, mast cell-deficient mice showed attenuated CXCL2 production and significantly reduced numbers of neutrophils, eosinophils, and B cells in the reproductive tract when compared with mast cell-containing littermates.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Taken together, these data demonstrate that mast cells are reactive to <jats:italic>Chlamydia<\/jats:italic> spp. through multiple mechanisms that include TLR2-dependent pathways. Mast cells also play an important role in shaping <jats:italic>in vivo<\/jats:italic> immune responses in <jats:italic>Chlamydia<\/jats:italic> reproductive tract infection through both effector cell recruitment and modification of the chemokine microenvironment.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1166068","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T06:00:54Z","timestamp":1681711254000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Mast cells selectively produce inflammatory mediators and impact the early response to Chlamydia reproductive tract infection"],"prefix":"10.3389","volume":"14","author":[{"given":"Animamalar","family":"Mayavannan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Shantz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian D.","family":"Haidl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean S.","family":"Marshall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,4,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0143304","article-title":"Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting","volume":"10","author":"Newman","year":"2015","journal-title":"PloS One"},{"key":"B2","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1038\/nrmicro.2016.30","article-title":"Chlamydia cell biology and pathogenesis","volume":"14","author":"Elwell","year":"2016","journal-title":"Nat Rev Microbiol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nri1551","article-title":"Immunology of chlamydia infection: implications for a chlamydia trachomatis vaccine","volume":"5","author":"Brunham","year":"2005","journal-title":"Nat Rev Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1086\/652397","article-title":"Pathogenesis of genital tract disease due to chlamydia trachomatis","author":"Darville","year":"2010","journal-title":"J Infect Dis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1439-0531.2012.02104.x","article-title":"Immunity and inflammation in the uterus","volume":"47","author":"Turner","year":"2012","journal-title":"Reprod Domest Anim"},{"key":"B6","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1111\/all.14881","article-title":"The ingenious mast cell: Contemporary insights into mast cell behavior and function","volume":"77","author":"Dahlin","year":"2022","journal-title":"Allergy"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.147.5.1621","article-title":"Human uterine mast cells. 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